Atherosclerosis is a leading cause of death and disability. Atherosclerosis is the narrowing of an artery lumen by an accumulation of “plaque” consisting of fat, cholesterol, calcium, cells and/or fibrin on the inside wall of the artery. The accumulation of plaque results in ischemia, an insufficient blood supply to meet the metabolic needs of an affected tissue bed. This can lead to heart attack, congestive heart failure, arrhythmia, stroke, kidney failure and loss of limbs.
Plaque accumulation in cerebral arteries can lead to transient ischemic events when blood flow is reduced to critical cerebral tissues. This can produce a form of ischemic stroke called thrombotic stroke. Symptoms are weakness, dizziness, confusion, slurred speech and vision impairment. These symptoms may not be severe and are temporary but they indicate that the patient is at risk for a more serious ischemic stroke.
Atherosclerosis also occurs in the peripheral arteries that feed the extremities. This can cause symptoms such as pain, numbness, ulcers and difficulty walking. Though these are seldom life threatening they do degrade the quality of life.
A screening technique is needed which will permit direct, non-invasive or minimally invasive diagnosis of atherosclerosis or of the predisposition of a patient to atherosclerosis. A number of techniques are available to diagnose atherosclerosis when there is advanced blood vessel blockage. They include angiography, magnetic resonance angiography and Doppler ultrasound. Angiography is invasive but provides an accurate image of any blockage. It is often used to diagnose atherosclerosis in coronary and cerebral arteries. Magnetic resonance angiography is less available and less accurate than angiography. Doppler ultrasound is non-invasive and can be used in most peripheral vasculature. Its use in cerebral vasculature somewhat limited. Each of these techniques detects or quantifies advanced atherosclerosis. They fail, however, to detect progressive atherosclerosis in early stages during decades of disease progression when a subject is free of symptoms and prior to the onset of major health impairment.
The arterial lumens throughout the body are lined with endothelial cells. The intact endothelium regulates a variety of physiologic functions including vasoconstriction and vasodilatation. Endothelial cells become damaged in the initial stage of atherosclerosis, decades before the development of obstructing plaque and clinical vascular disease. Damaged endothelial cells fail in a number of roles including physiologic vasodilatation. Traditional risk factors for atherosclerosis, including hypertension, smoking, diabetes and hypercholesterolemia, are all associated with impaired endothelial function. A linear relationship between endothelial dysfunction and atherosclerosis has been reported. (A. M. Zeiher, H. Drexler, H. Wollschlager, H. Just, “Modulation of the Coronary Vasomotor Tone in Humans: Progressive Endothelial Dysfunction with Different Early Stages of Atherosclerosis”, Circulation 1991; 83:391-401.) Diagnosis of endothelial dysfunction could expand the use of therapies known to decrease cardiovascular events. In patients with diagnosed cardiovascular disease an endothelial evaluation could be used to judge the efficacy of therapeutic interventions.
Non-invasive evaluation of endothelial function has been a challenging endeavor. One of the most commonly employed non-invasive techniques is brachial artery reactivity. With this technique blood flow is challenged mechanically or pharmaceutically and afterward the reactive augmented arterial flow is measured. For example, the subject's upper arm may be occluded for about five minutes by inflation of a blood pressure cuff and then released by deflation of the cuff. Deflation of the cuff results in a substantial transient increase in blood flow. After deflation, the brachial artery diameter is measured with a two-dimensional ultrasound and Doppler ultrasound. Measurements recorded at baseline are compared with reactive augmented flow occurring after deflation of the blood pressure cuff. Healthy subjects are found to experience about a twenty percent increase in brachial artery diameter and about a sixty percent increase in blood flow. With endothelial dysfunction, vessel diameter may increase five percent or less and the subject may experience an increase in blood flow of less than twenty-five percent. The test is accurate when performed in dedicated research laboratories in small numbers of patients. However, this technique requires expensive ultrasound equipment, an experienced ultrasonogropher and approximately forty-five to sixty minutes per exam.